Targeted therapies directed against key oncogenic targets offer considerable promise for the treatment of cancer. For many targeted therapies however, it is not possible to predict how a given patient will respond to treatment. As a result, oncologists must monitor response to therapy, such that patients who do not respond can quickly be switched to an alternative treatment regimen. If a patient does respond, a second problem then arises: how best to detect the onset of resistance as early as possible during the course of treatment. Such “early resistance detection” is an important clinical problem, and one that has been relatively unexplored to date. In this regard, the use of anti-EGFR therapeutics in cancers such as non-small cell lung cancer (NSCLC) provides a compelling example of the challenges facing oncologists in managing patients who will inevitably acquire resistance to treatment.
Patients with NSCLC exhibiting specific mutations in the EGFR domain often show a significant response to the anti-EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib (Iressa®) and erlotinib (Tarceva®). Estimates indicate over 70% of NSCLC patients with EGFR-mutant tumors show a decrease in tumor burden following treatment with either of the aforementioned TKIs. However, lung tumors in patients treated with these agents often eventually acquire resistance to this form of therapy, with a median time to treatment failure of ten months. Once therapeutic resistance develops, the treatment regimen should be re-evaluated as soon as possible, and potentially modified. Modification may include switching the patient to a different therapy or stopping treatment with the anti-EGFR TKI for a period of time in the hope of re-sensitizing the tumor to the original therapy.
Presently, the dominant approach to therapy monitoring in the clinic is based on the use of serial imaging scans during treatment. In the case of NSCLC patients receiving anti-EGFR therapy, computed tomography (CT) scans are typically performed every two months. Despite the wide spread use of imaging to monitor treatment response, it suffers from a number of serious drawbacks that ultimately limits its effectiveness. Specifically, imaging scans are time-intensive, relatively costly, and, in the case of CT, expose the patient to ionizing radiation. Furthermore, the molecular changes that drive therapeutic response and the development of resistance may occur sometime before their effects are apparent on imaging or morphological imaging (using, for example, the standard RECIST criteria).